Abstract：
BACKGROUND: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax.
METHODS: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination.
RESULTS: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001).
CONCLUSIONS: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.
METHODS: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination.
RESULTS: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001).
CONCLUSIONS: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.
摘要：
背景：BCR的双重抑制：ABL1酪氨酸激酶和BCL-2可能潜在地加深慢性粒细胞白血病慢性期（CML-CP）的应答率。本研究评估了达沙替尼和维奈托克联合用药的安全性和有效性。
方法：在这项2期试验中，患有CML-CP或加速期(克隆演变)的患者接受达沙替尼50mg/天,共3个疗程;在第4疗程加用维奈托克,共3年.维奈托克的初始剂量为200毫克/天，但后来减少到200毫克/天，持续14天，并在达到分子反应（MR）4.5后，以100mg/天的剂量，每疗程7天。经过3年的结合，患者接受达沙替尼单药治疗.主要终点是联合用药12个月时的主要分子反应率(MMR)。
结果：65例患者接受治疗。他们的平均年龄为46岁(范围，23-73).到12个月的组合，MMR,MR4和MR4.5的发生率为86%,53%,45%,分别。经过42个月的中位随访，4年无事件生存率和总生存率分别为96%和100%，分别。组合的结果与单药达沙替尼的历史结果相当（两种策略的累积12个月MMR率为79％）。联合用药的3-4级中性粒细胞减少症的发生率为22%，单药达沙替尼的发生率为11%(p<.001)。
结论：达沙替尼和维奈托克治疗CML-CP安全有效。该组合的累积缓解率与单药达沙替尼相似。需要进一步的随访以评估持久的深层分子反应和无治疗缓解的比率。
方法：在这项2期试验中，患有CML-CP或加速期(克隆演变)的患者接受达沙替尼50mg/天,共3个疗程;在第4疗程加用维奈托克,共3年.维奈托克的初始剂量为200毫克/天，但后来减少到200毫克/天，持续14天，并在达到分子反应（MR）4.5后，以100mg/天的剂量，每疗程7天。经过3年的结合，患者接受达沙替尼单药治疗.主要终点是联合用药12个月时的主要分子反应率(MMR)。
结果：65例患者接受治疗。他们的平均年龄为46岁(范围，23-73).到12个月的组合，MMR,MR4和MR4.5的发生率为86%,53%,45%,分别。经过42个月的中位随访，4年无事件生存率和总生存率分别为96%和100%，分别。组合的结果与单药达沙替尼的历史结果相当（两种策略的累积12个月MMR率为79％）。联合用药的3-4级中性粒细胞减少症的发生率为22%，单药达沙替尼的发生率为11%(p<.001)。
结论：达沙替尼和维奈托克治疗CML-CP安全有效。该组合的累积缓解率与单药达沙替尼相似。需要进一步的随访以评估持久的深层分子反应和无治疗缓解的比率。
